Voting

Accelerating the research to find suitable viral vectors and delivery systems to inhale gene therapy deeply into the lungs. Distal therapy is important for several fatal lung diseases. This is urgent and critical research.

Voting

Newer therapies using gene correction, rather than gene addition, are needed for sickle cell disease. Even with this potential advantage, there needs to be a way to safely deliver gene corrected HSC to the sickle cell patient. Chemotherapy is poorly tolerated, and often is the reason patients do not choose the BMT option. What is the status of other less toxic non myeloablative approaches, and how can they best be
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Inherited monogenic hematologic diseases such as hemophilia, beta-thalassemia and sickle cell disease are prime targets for future application of genome editing technology. However, studies are still needed to advance our understanding of the biology of genome editing as well as determine which other disorders are amenable to genome editing correction. Emphasis on preclinical research that focuses on determining the accuracy, safety and efficiency of this technology in order to help minimize off-target mutations and reduce toxicity, is essential for effective translation of this technology into the clinic. Once preclinical efficacy is established, support will be needed for clinical vector production, toxicity testing of the vectors/reagents used, and the performance of clinical trials. The gene correction strategies developed for inherited disorders will also be attractive for other hematologic diseases, and autoimmune disorders like lupus, rheumatoid arthritis, and type I diabetes). There is also a critical need for supporting preclinical validation studies, scale-up and GMP cell manufacturing, all of which could be shared infrastructures across multiple diseases in the NHLBI portfolio.

Name of idea submitter and other team members who worked on this idea:
Alice Kuaban on behalf of the American Society of Hematology (ASH)

Although targeted therapy is generally applied to the use of small molecules that target specific genes or proteins of diseased cells, it is now possible to target immune cells against specific diseases through genetic modification. This provides desired antigen-specificity to powerful cell-mediated cytotoxicity effects. Small studies show impressive results both in blood cancers and viral infections refractory to other therapies. Toxicity and efficacy vary with the diseases being treated and the cell products used. In addition, new approaches to genetically-modify blood stem cells are being evaluated to prevent viral infection, i.e. HIV, or correct hematopoietic stem cell derivatives, and these approaches could cure diseases for which good treatments are not currently available.

Feasibility and challenges of addressing this CQ or CC:

Both preclinical and clinical studies are needed to identify optimal cell types and gene constructs, use of “universal” donors, and magnitude and durability of clinical effects. Effective infrastructure to provide the right cells at the right time is necessary to test clinical efficacy.

Name of idea submitter and other team members who worked on this idea:
Mary Horowitz

Voting

There is a need to translate these new insights of genetic, molecular, cellular, and tissue arrhythmia mechanisms into the development of novel, safe, and new therapeutic interventions for the treatment and prevention of cardiac arrhythmias.

Reduced socioeconomic burden of cardiac arrhythmias. Development of new technologies and recognition of new arrhythmia mechanisms.

Feasibility and challenges of addressing this CQ or CC:

Several studies have already recognized the unexpected antiarrhythmic effects of some therapies intended for other cardiovascular disease. For example statins, aldosterone blockers, and possibly some essential fatty acids may reduce arrhythmia burden in patients receiving these interventions. Clinical trials should be developed to demonstrate the efficacy of these interventions, and arrhythmia endpoints, including those for atrial fibrillation and sudden cardiac death, should be incorporated into other large clinical trials. Research into novel antiarrhythmic might focus on (a) drug development; (b) cell/gene-based therapy and tissue engineering; and (c) improvements in development and use of devices and ablation to prevent or inhibit arrhythmic electrical activity. Continued research might also focus on targeting of upstream regulatory cascades of ion channel expression and function. Continued antiarrhythmic strategies might include the exploration of novel delivery systems (e.g., utilizing advances in nanotechnology and microelectronics), biological pacemakers, AV node repair/bypass, and treatment and/or reversal of disease-induced myocardial remodeling and tachyarrhythmias. Evaluation of new therapies should include a cost analysis. Studies in both children and adults with congenital heart are needed. New interventions might include new pharmacologic approaches as well as advances in electrophysiologic imaging and improved approaches to ablation.

Name of idea submitter and other team members who worked on this idea:
NHLBI Staff

Voting

There is a need to examine the use of recombinant DNA to the heart for correction of genetic abnormalities or restoration of normal signaling pathways to prevent heart failure. However, gene therapy is a complex process and more studies are needed in which tissue targeting, route of delivery, regulation of target gene expression, therapeutic dose, and identification of robust biomarkers are further investigated.

Successful gene therapy could restore or improve the condition of heart failure patients, especially when medications have been unsuccessful.

Feasibility and challenges of addressing this CQ or CC:

There have already been human trials of gene therapy in heart failure patients with positive outcomes.

Improvements in cardiac revascularization and medical therapies have significantly reduced cardiovascular-related deaths; however, the number of patients developing heart failure (HF) has steadily increased. One explanation is that surgery and medical therapies are palliative, but do not address the molecular pathogenesis of HF.

Name of idea submitter and other team members who worked on this idea:
NHLBI Staff

Voting

What are the best inroads for the NHLBI to support innovative approaches in the next 5-10 years, especially blood cell therapies based on hematopoietic stem cell and novel gene therapy approaches to control or even cure HIV infection?

HIV control or possibly even HIV cure could result from developing novel cell therapies, especially hematopoietic stem cell (HSC) transplants, and might also result from early use of antiretroviral therapy in acutely HIV-infected individuals.

• Transplantation of HSC including engineered cells has the potential to eradicate HIV reservoirs for HIV cure: the Berlin patient treated with HSC transplant remains free of HIV and is still the only patient cured of HIV infection as of today;

• Identification of acute HIV infections through routine blood donor screening and early anti-retroviral therapy for identified HIV-infected donors can limit or even prevent the establishment of HIV reservoirs.

Feasibility and challenges of addressing this CQ or CC:

• The Berlin patient has provided the proof of concept that HIV infection can be eradicated, that is, sterilizing cure can be achieved, through HSC transplantation in combination with other therapies;

• Recent studies have shown that early identification of HIV infection and treatment of infected individuals with anti-retroviral therapy as soon as possible can significantly limit the size of the HIV reservoirs even if such early treatment may not be able to completely prevent the establishment of HIV reservoirs; routine blood donor screening for both anti-HIV antibodies and HIV RNA among blood donors offers unique opportunities to identify acute HIV infections.

For HIV cure, the challenges include:

• Generation of HIV-resistant HSCs in adequate quantity for transplantation;

• Efficiency of homing and expansion of HIV-resistant HSC transplants;

• Efficiency in replacing HIV-infected cells, including CD4+ resting cells as the major HIV reservoirs, with HIV-resistant HSCs following transplantation;

Voting

What methodologies will best enhance the translation of technologies for gene and cell therapies into potential products for clinical application and commercial development?
In considering a strategy for NHLBI investment in gene therapy, it is important to note that we are only at the beginning of a revolution that will eventually impact biomedical research across a broad range of specialties. NHLBI/NIH needs to create
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Technological advances in vector discovery over the last decade have set the stage for a wave of potential clinical successes in diseases relevant to NHLBI. These advances include the use of lentiviral vectors for bone marrow directed gene therapy with thalassemia emerging as an attractive target and with compelling clinical data with novel AAV serotypes in the treatment of hemophilia B, and possibly hemophilia A in the future.

Furthermore, an important milestone was achieved in November 2012 with the approval of the AAV-based product Glybera by the European Medicines Agency for the treatment of a rare form of hypertriglyceridemia. This first and only commercially approved gene therapy product demonstrated regulatory receptivity for gene therapy which fueled a long overdue investment by the biopharmaceutical industry in gene therapy.

Finally, gene editing technologies such as CRISPR (clustered, regularly interspersed short palindromic repeats) are most suited for ex vivo approaches of gene therapy such as those based on engineered bone marrow stems cells for diseases like sickle cell anemia. These types of approaches could substantially reduce the risk of insertional mutagenesis that plagues lentiviral vectors and could improve expression profiles of the corrected cells by utilizing endogenous regulatory sequences.

Feasibility and challenges of addressing this CQ or CC:

It is increasingly being recognized that establishing standardized assays for evaluating product potency and purity such as “pharmacologic” regulation will be critical for the success of gene therapy. NHLBI/NIH can also play a significant role in the development of second generation gene therapy technologies with enhanced safety and efficacy.

Name of idea submitter and other team members who worked on this idea:
NHLBI Staff

To extend our knowledge of the pathobiology of heart, lung, blood, and sleep disorders and enable clinical investigations that advance the prediction, prevention, preemption, treatment, and cures of human disease.